Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare lysosomal storage disorders caused by deficient acid ceramidase (ACDase) activity. Although both conditions are caused by mutations in the ASAH1 gene, clinical presentations differ considerably. FD patients usually die in childhood, while SMA-PME patients can live until adulthood. There is no treatment for FD or SMA-PME. Hematopoietic stem cell transplantation (HSCT) and gene therapy strategies for the treatment of ACDase deficiency are being investigated. We have previously generated and characterized mouse models of both FD and SMA-PME that recapitulate the symptoms described in patients. Here, we show that HSCT improves lifespan, behavior, hematopoietic system anomalies, and plasma cytokine levels and significantly reduces histiocytic infiltration and ceramide accumulation throughout the tissues investigated, including the CNS, in both models of ACDase-deficient mice. HSCT was also successful in preventing lesion development and significant demyelination of the spinal cord seen in SMA-PME mice. Importantly, we note that only early and generally pre-symptomatic treatment was effective, and kidney impairment was not improved in either model.

• MeSH
• ceramidy metabolismus   MeSH
• Farberova nemoc * terapie   genetika   MeSH
• kyselá ceramidasa * genetika   metabolismus   MeSH
• lidé MeSH
• mícha metabolismus   patologie   MeSH
• modely nemocí na zvířatech MeSH
• myoklonické epilepsie progresivní genetika   terapie   metabolismus   MeSH
• myši knockoutované MeSH
• myši MeSH
• transplantace hematopoetických kmenových buněk * metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The development and progression of colorectal cancer (CRC), a major cause of cancer-related death in the western world, is accompanied with alterations of sphingolipid (SL) composition in colon tumors. A number of enzymes involved in the SL metabolism have been found to be deregulated in human colon tumors, in experimental rodent studies, and in human colon cancer cells in vitro. Therefore, the enzymatic pathways that modulate SL levels have received a significant attention, due to their possible contribution to CRC development, or as potential therapeutic targets. Many of these enzymes are associated with an increased sphingosine-1-phosphate/ceramide ratio, which is in turn linked with increased colon cancer cell survival, proliferation and cancer progression. Nevertheless, more attention should also be paid to the more complex SLs, including specific glycosphingolipids, such as lactosylceramides, which can be also deregulated during CRC development. In this review, we focus on the potential roles of individual SLs/SL metabolism enzymes in colon cancer, as well as on the pros and cons of employing the current in vitro models of colon cancer cells for lipidomic studies investigating the SL metabolism in CRC.

• MeSH
• alkalická ceramidasa genetika   metabolismus   MeSH
• ceramidy metabolismus   MeSH
• fosfotransferasy s alkoholovou skupinou jako akceptorem genetika   metabolismus   MeSH
• kyselá ceramidasa genetika   metabolismus   MeSH
• laktosylceramidy metabolismus   MeSH
• lidé MeSH
• lysofosfolipidy metabolismus   MeSH
• metabolismus lipidů genetika   MeSH
• modely nemocí na zvířatech MeSH
• nádorové buňky kultivované MeSH
• nádory tračníku enzymologie   genetika   patologie   MeSH
• neutrální ceramidasa genetika   metabolismus   MeSH
• protoonkogenní proteiny c-akt genetika   metabolismus   MeSH
• regulace genové exprese u nádorů * MeSH
• sfingolipidy metabolismus   MeSH
• sfingosin-N-acyltransferasa genetika   metabolismus   MeSH
• sfingosin analogy a deriváty   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Farber disease (FD) is a debilitating lysosomal storage disorder characterized by severe inflammation and neurodegeneration. FD is caused by mutations in the ASAH1 gene, resulting in deficient acid ceramidase (ACDase) activity. Patients with ACDase deficiency exhibit a broad clinical spectrum. In classic cases, patients develop hepatosplenomegaly, nervous system involvement, and childhood mortality. Ocular manifestations include decreased vision, a grayish appearance to the retina with a cherry red spot, and nystagmus. That said, the full effect of ACDase deficiency on the visual system has not been studied in detail. We previously developed a mouse model that is orthologous for a known patient mutation in Asah1 that recapitulates human FD. Herein, we report evidence of a severe ocular pathology in Asah1P361R/P361R mice. Asah1P361R/P361R mice exhibit progressive retinal and optic nerve pathology. Through noninvasive ocular imaging and histopathological analyses of these Asah1P361R/P361R animals, we revealed progressive inflammation, the presence of retinal dysplasia, and significant storage pathology in various cell types in both the retina and optic nerves. Lipidomic analyses of retinal tissues revealed an abnormal accumulation of ceramides and other sphingolipids. Electroretinograms and behavioral tests showed decreased retinal and visual responses. Taken together, these data suggest that ACDase deficiency leads to sphingolipid imbalance, inflammation, dysmorphic retinal and optic nerve pathology, and severe visual impairment.

• MeSH
• ceramidy genetika   metabolismus   MeSH
• Farberova nemoc * enzymologie   genetika   patologie   MeSH
• kyselá ceramidasa genetika   metabolismus   MeSH
• missense mutace * MeSH
• modely nemocí na zvířatech MeSH
• mutantní kmeny myší MeSH
• myši MeSH
• nervus opticus * enzymologie   patologie   MeSH
• poruchy zraku * enzymologie   genetika   patologie   MeSH
• retina * enzymologie   patologie   MeSH
• sfingolipidy genetika   metabolismus   MeSH
• substituce aminokyselin MeSH
• zánět enzymologie   genetika   patologie   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Farber disease is a rare autosomal recessive disorder caused by acid ceramidase deficiency that usually presents as early-onset progressive visceral and neurologic disease. To understand the neurologic abnormality, we investigated behavioral, biochemical, and cellular abnormalities in the central nervous system of Asah1(P361R/P361R) mice, which serve as a model of Farber disease. Behaviorally, the mutant mice had reduced voluntary locomotion and exploration, increased thigmotaxis, abnormal spectra of basic behavioral activities, impaired muscle grip strength, and defects in motor coordination. A few mutant mice developed hydrocephalus. Mass spectrometry revealed elevations of ceramides, hydroxy-ceramides, dihydroceramides, sphingosine, dihexosylceramides, and monosialodihexosylganglioside in the brain. The highest accumulation was in hydroxy-ceramides. Storage compound distribution was analyzed by mass spectrometry imaging and morphologic analyses and revealed involvement of a wide range of central nervous system cell types (eg, neurons, endothelial cells, and choroid plexus cells), most notably microglia and/or macrophages. Coalescing and mostly perivascular granuloma-like accumulations of storage-laden CD68(+) microglia and/or macrophages were seen as early as 3 weeks of age and located preferentially in white matter, periventricular zones, and meninges. Neurodegeneration was also evident in specific cerebral areas in late disease. Overall, our central nervous system studies in Asah1(P361R/P361R) mice substantially extend the understanding of human Farber disease and suggest that this model can be used to advance therapeutic approaches for this currently untreatable disorder.

• MeSH
• časové faktory MeSH
• centrální nervový systém abnormality   patologie   MeSH
• chování zvířat MeSH
• Farberova nemoc komplikace   patologie   MeSH
• fenotyp MeSH
• homozygot MeSH
• hydrocefalus patologie   MeSH
• kyselá ceramidasa metabolismus   MeSH
• malformace nervového systému etiologie   patologie   MeSH
• mozeček patologie   ultrastruktura   MeSH
• myši transgenní MeSH
• myši MeSH
• neurony patologie   ultrastruktura   MeSH
• pohybová aktivita MeSH
• sfingolipidy metabolismus   MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
• velký mozek patologie   ultrastruktura   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH